Efficacy and safety of fire needle combined with cupping for acute herpes zoster and postherpetic neuralgia: A protocol for systemic review and meta-analysis

Background: Herpes zoster and post-herpetic neuralgia showed an increasing incidence during past two decades. Most of herpes zoster and post-herpetic neuralgia patients suffered from pain, anxiety, and depression. Fire needle combined with cupping is becoming a popular way to relieve the pain caused by herpes zoster and decrease the incidence of post-herpetic neuralgia. In this study, we aim to investigating the efficacy and safety of fire needle combined with cupping for the treatment of acute herpes zoster and postherpetic neuralgia (PHN). Methods: The literature search will be carried out in following databases: PubMed/MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Wanfang Data. Published and unpublished controlled trials compared fire needle combined with cupping to other treatments for acute herpes zoster or PHN will be included. Data from eligible studies will be extracted by 2 independent reviewers. Different scales will be used to assess the risk of bias based on the study design. Pain intensity and PHN are primary outcomes. The final effect size will be reported using 95% confidence interval at 0.05 significance level. Discussion: This review will provide certain evidence to compare the efficacy and safety of combined acupuncture and cupping with guideline recommended drug or nerve block therapy for the treatment of herpes zoster and post-herpetic neuralgia. It will potentially provide more clinical suggestions and guidelines for health care professionals, policymakers, and researchers.


Introduction
Herpes zoster (HZ), also known as Shingles, is one of the most common skin infection diseases caused by the varicella-zoster virus. [1] The virus usually stays inactive near spinal cord or brain in the nerve tissues after the first time infected, usually during childhood, and this virus can reactivate years later, causing HZ accompanied by severe neuralgia. [2,3] Postherpetic neuralgia (PHN) usually appears after the patient's herpes has healed near the skin lesion, it is a kind of refractory neuralgia that can last for a long time after the onset of HZ. [4,5] The incidence of HZ during 1994 and 2018 increased from 2.86% to 5.79%, and the percentage of patients with HZ that developed PHN also showed an increasing trend from 1994~2006 to 2007~2018 in North America, Europe, and Asia-Pacific. [4] It was reported that the pain related to HZ and PHN has significant effect in the quality of life of the affected patients, around 45% of these patients may suffer from anxiety, depression, and lack of concentration. [6] HZ is usually considered to be a self-limiting disease in immunocompetent patients, antiviral therapies was recommended SH and YX contributed equal to this work. If amendments are needed, the authors will update their protocol to include any changes in the whole process of research. Medicine to hasten healing time while paracetamol/acetaminophen was used for significant pain management over 50 years. [7] However, there is no evidence showed that antiviral therapies has any positive effect on reducing the incidence of PHN. [8] In addition to non-steroidal anti-inflammatory drugs, glucocorticoid, nerve-blocking therapy, mental and psychological intervention were also used for HZ and PHN related pain relief. [9][10][11] It is noteworthy that all these treatments shows unstable effect in pain management, and may increase the renal burden and impact the immune system, especially for those with renal insufficiency or immunodeficiency.
Recently, acupuncture, especially fire needle, has been reported to be an effective method for pain relief during past few decades, and it could provide notable benefit for the patients in the acute stage of HZ and PHN. [12] Acupuncture could stimulate acupuncture points to relieve local pain and spasm, and then promote local blood circulation and dredge the meridians. Besides, acupuncture was also recommended as Chinese clinical practice guidelines for HZ and PHN by the Chinese Consensus of Diagnosis and Treatment of HZ and PHN. Moreover, acupuncture are frequently used combined with thermotherapy in clinical practice. [12,13] Fire needle is one of the most common acupuncture that used for the treatment of acute HZ and PHN, several studies showed that fire needle could significantly reduce the incidence of PHN. [14] Additionally, cupping therapy was also found to effectively relieve pain by promoting local microcirculation and decreasing the expression of pain-causing substances. [15] Nowadays, it is becoming popular combining fire needle and cupping together for pain management in China. Increasing studies showed fire needle combined with cupping treatment could remarkably enhance the efficacy of fire needle and dramatically reduce HZ and PHN related pain, shorten the pain duration and decrease the incidence of PHN. [12] Nevertheless, the superiority of fire needle plus cupping in the treatment of HZ and PHN is still not clear when comparing to guideline drug, block therapy or fire needle treatment only. To acquire a comprehensive understanding of the efficacy and safety of fire needle combined with cupping therapy when treating with HZ and PHN patients, we conducted this systematic review and meta-analysis, in which we aimed to providing suggestions as well as guidance for clinical practice.

Methods and analysis
This review was conducted in coincidence with previous developed protocol that registered on the National Institute of Health Research Database (CRD42022300076). This review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. [16] 2.1. Inclusion criteria a) Types of studies: Randomized-controlled studies (RCTs), non-randomized-controlled-studies (NRSs), cohort studies and case-control studies. b) Patients: Adults with acute HZ (<7 days from onset), or adults that diagnosed as PHN and suffered from sustained pain for >3 months. [17]

Exclusion criteria
a) Case report, case series, and reviews. b) Abstract or conference with incomplete limited data. c) Patients with HZ complications including HZ meningoencephalitis, Ramsay Hunt syndrome, zoster opthalmicus (combined with conjunctivitis, keratitis or scleritis), visceral or disseminated zoster, Vernet syndrome, and concomitant bacterial infections. d) Patients used HZ vaccine as adjunct to intervention or control treatment.

Search strategy
The literature search will be carried out in following databases: Additional studies will be identified through the references of included studies. The flow chart for this systematic review is described in Figure 1. A separate searching strategy will be developed for each database with following keywords and related terms: (fire needle OR fire acupuncture OR red hot needle OR burn needle) AND (cupping OR wet cupping OR dry cupping OR pricking cupping OR moving cupping OR flash cupping) AND (HZ OR shingles OR postherpetic neuralgia OR PHN OR herpetic neuralgia).
Anticipated date: March 2023 to August 2023.

Data extraction
All the retrieved records will be imported to EndNote X8. After removing duplicate studies, title and abstract will be screened and checked independently at least by 2 reviewers and the full text of identified researches will be further assessed for eligibility. Following characteristics will be collected: author name, publication year, study design, gender distribution, sample size, publishing region, follow-up duration, clinical diagnosis, interventions, major outcomes and measures of interest. Any discrepancies on primary article data collection or critical appraisal will lead to consult the third reviewer.

Risk of bias assessment
According to different types of study design, corresponding scales will be applied to evaluate the risk of bias by 2 independent reviewers. Cochrane criteria, Methodological Index for Non-Randomized Studies and Newcastle-Ottawa scale will be used for RCTs, cohort (or case control) studies and NRSs evaluation, respectively.

Assessing certainty in the findings
The methodological quality of each evidence will be assessed via the 2009 Oxford Centre for Evidence-based Medicine Levels of Evidence or Grading of Recommendations, Assessment, Development, and Evaluation approach. [18]

Data analysis
All the statistical analyses will be done by RevMan software (version: 5.3) or STATA Analytical Software (version 14, StataCorp). For dichotomous variables, odds ratio will be used for data synthesis from case-control studies, while risk ratio using the Mantel-Haenszel test will be used for RCTs and NRSs. In contrast, weighted mean difference will be applied for continuous variables using inverse variance method if the combined measures were numerically similar. If not, standard mean difference will be applied instead. All the pooled effect will be displayed using 95% confidence interval with a significance level of 0.05. Missing data will be retrieved by contacting with related corresponding authors. Those studies that are not eligible for meta-analysis will be discussed using a narrative synthesis approach. Chi-square test (I 2 statistic) will be used for the evaluation of data heterogeneity, I 2 < 10% will be considered with low heterogeneity. In order to detecting potential clinical heterogeneity, meta-regression or Galbraith plot will be carried out. Subgroup analysis will be applied according to study design, age of included patients, intervention or control characters to minimize related clinical heterogeneities. Random effects model will be used for all the meta-analysis that with remarkable heterogeneity (25%). Sensitivity analysis will be conducted by sequential removal of each single study from the analysis.
Publication bias will be assessed by funnel plot, Egger's weighted liner regression test or Harbord test at a 5% significance level for the meta-synthesis containing >10 studies. Discrepancies between reviewers will be resolved by consulting the third reviewer. Trim and fill analysis will be done for the synthesis with significant publication bias, and adjusted effect sizes will be reported.

Discussion
HZ and PHN showed an increasing incidence during past two decades, both HZ and PHN will bring remarkable negative impact on the patients' quality of life, daily activities and economic well-being of patients. [3,19,20] Although drug or nerve block therapy was recommended for the pain management in HZ and PHN patients nowadays, approximately half patients may still not get sufficient and satisfactory pain relieve. [21] Besides, few worldwide suggested front-line therapy for PHN including antiepileptics will still bring few side-complications.
Acupuncture and cupping have a prominent place Chinese traditional medicine and has a theatrical history of >2000 years. Recently, fire needle plus cupping was suggested for the treatment of HZ an PHN in China, but no high quality synthesis study was conducted. Therefore, we conducted this systematic review and meta-analysis, hoping to provide more clinical suggestions and guidelines for the treatment of HZ and PHN.

Strengths and limitations of this study
This is the first systematic review and meta-analysis protocol designed to investigate the efficacy and safety of fire needle combined with cupping for the treatment of both acute HZ and PHN. The protocol is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols checklist, and we provided detailed heterogeneity management. In addition, comprehensive and specific risk of bias assessment will be conducted for different study design. However, this review has potential limitations. The language of studies will be restricted to English and Chinese, meaning that evidence published in any other language will be missed.

Author contributions
All authors read and approved the final manuscript.